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Acute Kidney Injury (AKI) - Basic to Advanced

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1. Definition & Epidemiology

• Serum creatinine (sCr) rises ≥0.3 mg/dL within 48 hours
• sCr rises to ≥1.5x baseline within 7 days
• Urine output (UO) <0.5 mL/kg/h for >6 hours

• Affects ~10-15% of all hospitalized patients
• Rises to 55-65% of ICU patients
• Community-acquired AKI is uncommon: <1% annual incidence
• AKI requiring dialysis has increased substantially over the past three decades
• AKI is also frequently undiagnosed in low-resource settings worldwide

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2. Diagnostic Criteria & Staging

RIFLE / AKIN / KDIGO Comparison

KDIGO Staging

In children <18 years, Stage 3 also includes eGFR <35 mL/min/1.73 m²

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3. Classification: Prerenal / Intrinsic / Postrenal

A. Prerenal AKI (40-55% of cases; 60-70% community-acquired)

• Reduced effective arterial blood volume (EABV) triggers baroreceptors
• Cascade: sympathetic activation → catecholamines → ADH release → RAAS activation
• Angiotensin II preferentially constricts the efferent arteriole to preserve GFR
• Severe/prolonged hypoperfusion → afferent constriction → GFR falls → ischemic ATN

• True hypovolemia: hemorrhage, GI losses (vomiting, diarrhea), overdiuresis, third-spacing (pancreatitis), burns
• Decreased EABV without total body depletion: cardiogenic shock, septic shock, cirrhosis, hypoalbuminemia, anaphylaxis
• Volume-nonresponsive prerenal: CHF, liver failure, sepsis - IV fluids won't restore renal perfusion here

• BUN:Cr ratio >20:1 (urea back-diffusion due to ADH)
• FENa <1% (avid sodium retention)
• Urine osmolality >500 mOsm/kg
• Urine sodium <20 mEq/L
• Specific gravity >1.020

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B. Intrinsic AKI (25-40% hospital; up to 60% in ICU)

Subtypes:

• Ischemic ATN: Continuation of severe prerenal; ischemia + reperfusion injury → tubular cell death, cast formation, tubular obstruction, back-leak of filtrate
• Toxic ATN: Common nephrotoxins include:
  • Antimicrobials: aminoglycosides, vancomycin, amphotericin B, acyclovir, tenofovir
  • Contrast agents: radiocontrast nephropathy (risk x10 in CKD/volume-depleted patients)
  • Endogenous toxins: myoglobin (rhabdomyolysis), hemoglobin (hemolysis), uric acid, calcium oxalate
  • Drugs: cisplatin, cyclosporine, tacrolimus, methotrexate
• Septic AKI: inflammatory cytokines drive renal vasoconstriction + direct tubular injury

• Drugs (most common): sulfonamides, penicillins, cephalosporins, NSAIDs, PPIs, checkpoint inhibitors (in ~5% of treated cancer patients)
• Infections: Legionella, leptospirosis, Yersinia, Streptococcus, TB, SARS-CoV-2, CMV, EBV
• Systemic disease: SLE, Sjögren syndrome, cryoglobulinemia
• Classic triad (fever + rash + eosinophilia) is present in <30% of cases

• Rapid-progressive GN (RPGN), vasculitis, lupus nephritis, anti-GBM disease

• TTP/HUS, malignant hypertension, renal artery occlusion, cholesterol emboli

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C. Postrenal AKI (5-10%)

• Lower urinary tract (most common): BPH, prostate cancer, bladder cancer, cervical cancer, neurogenic bladder (diabetes, spinal cord disease)
• Ureteral (bilateral): retroperitoneal fibrosis, endometriosis, metastatic colon cancer, lymphoma
• Intraluminal: bilateral renal calculi, papillary necrosis, blood clots

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4. Pathophysiology of Ischemic ATN (Advanced)

1. Microvascular compartment: Intense renal vasoconstriction - especially afferent arteriolar constriction reduces renal blood flow; endothelial activation promotes leukocyte adhesion
2. Tubular injury:
   • Proximal tubular cells lose polarity; Na-K-ATPase redistributes from basolateral to apical membrane
   • Loss of brush border
   • Sublethally injured cells shed apical membranes into the lumen → tubular casts → obstruction → back-pressure reduces GFR
   • Sublethally injured cells detach and are shed in urine (viable + necrotic)
3. Back-leak of filtrate: Damaged tubular epithelium loses integrity; glomerular filtrate leaks back across the tubular wall into the interstitium
4. Innate immunity activation: Ischemia triggers NF-κB → pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-18) → further vasoconstriction and tubular injury
5. Reperfusion injury: Paradoxically, restoration of flow generates reactive oxygen species (ROS) and activates complement, worsening injury

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5. Novel Biomarkers

Key principle: Urinary NGAL and KIM-1 are elevated in intrinsic AKI, but NOT in prerenal disease - making them useful for differentiating these two categories.

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6. Clinical Features

• Often asymptomatic early (detected by labs)
• Oliguria (<400 mL/day) or anuria (<100 mL/day) - but AKI can be non-oliguric
• Nausea, vomiting, fatigue, confusion (uremia)
• Fluid overload: peripheral edema, pulmonary edema, hypertension

• Hyperkalemia (most dangerous acutely - cardiac arrhythmias)
• Metabolic acidosis (non-anion gap initially, then elevated AG with uremia)
• Volume overload / pulmonary edema
• Hypo/hypernatremia
• Hypocalcemia + hyperphosphatemia

Important: Even 1 day of prerenal azotemia can produce hyponatremia, hyperkalemia, and acidosis with increased mortality. About 1/3 of hospitalized AKI cases resolve within 24 hours, ~60% by 48 hours, ~70% by 72 hours.

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7. Diagnostic Approach

Note: FENa can be <1% in early obstruction, contrast nephropathy, myoglobinuria, and AIN caused by NSAIDs - do not rely on it alone.

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8. Management

A. General Principles

1. Remove the offending cause - stop nephrotoxins (NSAIDs, ACEi/ARBs, aminoglycosides, contrast), treat infection, relieve obstruction
2. Volume status optimization - most patients need volume resuscitation, but avoid fluid overload (associated with worse outcomes). Balanced crystalloids (lactated Ringer's or PlasmaLyte) are preferred over normal saline (hyperchloremic metabolic acidosis risk)
3. Hemodynamic support - MAP target ≥65 mmHg; vasopressors in septic AKI
4. Electrolyte management - monitor K+, Na+, HCO3-, Phos, Ca2+ closely
5. Nutritional support - high catabolic state; avoid protein restriction
6. Drug dose adjustment - renally cleared drugs must be dose-adjusted

B. Specific Causes

• ATN: Supportive; no proven therapy reverses established ATN. Early removal of the insult is key
• Contrast nephropathy: Pre-hydration with IV isotonic saline; minimize contrast volume; use iso-osmolar contrast; N-acetylcysteine benefit uncertain
• AIN: Remove offending drug; corticosteroids (prednisolone 0.5-1 mg/kg/day) may accelerate recovery in drug-induced AIN if no improvement within 5-7 days
• Rhabdomyolysis: Aggressive IV fluid hydration (goal UO 200-300 mL/h); alkalinization of urine with sodium bicarbonate (controversial)
• Postrenal: Bladder catheterization or ureteral stenting; post-obstructive diuresis must be monitored

C. Avoiding Common Mistakes

• Do NOT give contrast without pre-hydration in at-risk patients
• Do NOT use nephrotoxic antibiotics when alternatives exist
• Do NOT withhold adequate volume resuscitation out of fear of fluid overload
• NSAIDs block prostaglandin-mediated afferent dilation - avoid in any patient at risk

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9. Renal Replacement Therapy (RRT)

When to start (KDIGO indications - "AEIOU"):

• Acidosis - metabolic acidosis pH <7.1 refractory to medical management
• Electrolytes - refractory hyperkalemia (K+ >6.5 or with ECG changes)
• Intoxication - dialyzable toxins (methanol, ethylene glycol, lithium, aspirin)
• Overload (volume) - refractory pulmonary edema
• Uremia - uremic encephalopathy, pericarditis, bleeding

Early vs. Delayed RRT (Key Trials):

RRT Modalities:

• Sessions 3-5 hours, blood flow 200-400 mL/min
• Good for stable patients; rapid solute clearance
• Risk: intradialytic hypotension (rapid fluid shifts); avoid in hemodynamically unstable patients
• Dialysis disequilibrium: use lower blood flows initially; hypertonic dialysate Na (145 mmol/L) for stability
• Avoid dialysate K+ <2 mmol/L (arrhythmia risk)

• Continuous venovenous hemofiltration (CVVH), hemodiafiltration (CVVHDF), or hemodialysis (CVVHD)
• Preferred for hemodynamically unstable patients
• Slow, continuous fluid/solute removal - better hemodynamic tolerability
• Requires continuous anticoagulation (regional citrate preferred; systemic heparin second choice)
• Dose: KDIGO recommends effluent volume of 20-25 mL/kg/h (actual delivered; order higher to account for downtime)
• Requires meticulous hourly fluid balance management

• Hybrid modality: longer sessions (6-12 h) at lower flow rates
• Intermediate hemodynamic tolerability; can be done overnight
• Good option when CRRT infrastructure unavailable

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10. Special Situations (Advanced)

Hepatorenal Syndrome (HRS-AKI)

• AKI in cirrhosis with portal hypertension; functional renal failure due to severe splanchnic vasodilation
• ICA criteria: AKI (sCr rise ≥0.3 mg/dL or ≥50%) in cirrhosis, no response to 2 days of volume expansion + diuretic withdrawal
• HRS-1 (now HRS-AKI): rapidly progressive (formerly AKF); HRS-2: more gradual
• Treatment: vasoconstrictors (norepinephrine or terlipressin) + albumin infusion; liver transplant is definitive

Cardiorenal Syndrome (CRS)

• Type 1 CRS: acute heart failure → AKI (right-sided congestion raises renal venous pressure; left-sided failure reduces cardiac output)
• Both reduced output AND venous congestion contribute independently to AKI
• Management: careful decongestion while maintaining renal perfusion; avoid excessive diuresis

Contrast-Induced AKI (CI-AKI)

• sCr rise within 48-72 hours of contrast exposure
• Risk factors: pre-existing CKD (eGFR <45), diabetes, volume depletion, NSAID/ACEi use, high contrast volume
• Prevention: IV isotonic crystalloid (1-1.5 mL/kg/h for 3-12 h pre- and post-procedure); iso-osmolar contrast; minimize volume; hold nephrotoxins

AKI in Sepsis

• Most common cause of AKI in the ICU (~50% of ICU AKI)
• Mechanism: combined hemodynamic (vasodilation + microvascular dysfunction) + direct inflammatory/cytokine-mediated tubular injury
• Fluid resuscitation with balanced crystalloids; vasopressors for MAP ≥65 mmHg
• Early source control is the most important intervention

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11. AKI-to-CKD Transition & Prognosis

• Mortality: Hospital mortality ~10-30%; ICU AKI mortality up to 50-60% depending on severity and comorbidities
• Recovery: ~70% of hospitalized AKI resolves within 72 hours; those requiring RRT have 30-60% in-hospital mortality
• AKI → CKD: AKI is a major risk factor for CKD development and progression - incomplete recovery leaves scar tissue (tubular atrophy + interstitial fibrosis)
• Risk of progression to CKD is proportional to AKI severity, number of AKI episodes, and degree of recovery
• AKI → cardiovascular events: AKI is independently associated with long-term cardiovascular morbidity (hypertension, heart failure)
• Post-discharge follow-up: all AKI patients should have kidney function checked at 3 months; those with AKD or incomplete recovery need nephrology referral

• Identify high-risk patients early (elderly, CKD, diabetes, CHF, hypovolemia)
• Avoid or minimize nephrotoxins
• Ensure adequate hydration before contrast/surgery
• Electronic AKI alert systems have been shown to improve detection and outcomes (Meta-Analysis, JAMA Network Open 2024, PMID: 39190304)

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12. Quick Summary Table

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Recent evidence update (2024-2026): Electronic AKI alert systems improve recognition and may improve outcomes (systematic review, PMID 39190304). Balanced crystalloids (vs. normal saline) continue to be supported in septic resuscitation with AKI (systematic review, PMID 39891147).